Pharmaceutical Sciences and Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Mol Pharm. 2012 Mar 5;9(3):605-14. doi: 10.1021/mp2005164. Epub 2012 Feb 8.
Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent, is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Three hydrophilic amide prodrugs of celecoxib, celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity were significantly lower than for celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10-20% conversion to parent celecoxib in 30 min. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5-fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 μM. Celecoxib succinamidic acid, a soluble prodrug of celecoxib with reduced melanin binding, enhances transscleral retinal delivery of celecoxib.
经巩膜递药将抗炎和抗 VEGF 药物塞来昔布递送至脉络膜-视网膜色素上皮（choroid-RPE）受到其溶解度低和与脉络膜黑色素结合的限制。本研究旨在开发塞来昔布的水溶性前药，以降低与黑色素的结合并增强视网膜递药。我们合成并鉴定了三种塞来昔布的亲水性酰胺前药：塞来昔布琥珀酸酰胺（CSA）、塞来昔布马来酸酰胺（CMA）和塞来昔布乙酰胺（CAA），以评估其溶解度和脂溶性。我们对这三种前药与天然黑色素（乌贼墨）的黑色素结合进行了体外评估。我们还进行了离体牛巩膜和巩膜-脉络膜-视网膜色素上皮（SCRPE）的体外转运研究。在 SCRPE 中具有最高通透性的前药用于代谢和细胞毒性特征分析及其在色素沉着大鼠的经巩膜递药。CSA、CMA 和 CAA 的水溶解度分别比塞来昔布高 300、182 和 76 倍。与塞来昔布相比，所有三种前药与黑色素的结合亲和力和容量均显著降低。体外经牛巩膜和 SCRPE 的转运百分率顺序为 CSA>CMA~CAA>塞来昔布，与塞来昔布相比，CSA 的转运率高 8 倍。我们进一步评估了 CSA 的代谢稳定性和体内递药。CSA 在所有眼部组织中显示出最佳的代谢稳定性，在 30 分钟内仅有 10-20%转化为母体塞来昔布。参与生物转化的代谢酶包括酰胺酶、酯酶和细胞色素 P-450。在色素沉着 BN 大鼠中的体内递药显示，CSA 向巩膜、脉络膜-RPE、视网膜、玻璃体和晶状体的递药分别比塞来昔布高 4.7、1.4、3.3、6.0 和 4.5 倍。CSA 在 0.1 至 1000 μM 的浓度范围内对 ARPE-19 细胞无细胞毒性。塞来昔布琥珀酸酰胺是塞来昔布的一种水溶性前药，与黑色素的结合减少，增强了塞来昔布的经巩膜视网膜递药。
